1. Breast Cancer and Bone Health
Robert Coleman,
Cancer Research Centre,
Weston Park Hospital,
Sheffield

2. Breast Cancer and Bone Health
Normal Bone Health
Impact of Cancer Therapies on Bone Health
Therapeutic Strategies
Management Guidelines

3. Breast Cancer and Bone Health
Normal Bone Health
Impact of Cancer Therapies on Bone Health
Therapeutic Strategies
Management Guidelines

4. The Structure of Bone Cortical Bone Vascular Supply Trabecular Bone
Marrow

5. Properties of the skeleton
Skeleton composition:
80% cortical bone (mostly in the appendicular skeleton)
20% trabecular bone (mostly in the axial skeleton)
Trabecular bone:
large surface area / unit volume
highly responsive to metabolic processes
turnover is 8x that of cortical bone
more sensitive for measuring changes in BMD due to bone loss or therapy
annual turnover rate of 25% compared with 5–6% for cortical bone.
Fractures commonly occur in trabecular bone
(e.g. vertebra, femoral neck, distal radius).

6. Bone Remodeling
Osteoclast
Osteoblasts 6

7. Bone Remodeling

8. Components of Bone Strength
quality
Bone
density +
Architecture
Bone turnover
Accumulation of lesions (microfractures)
Secondary mineralisation
aBMD = g/cm2
vBMD = g/cm3
This slide summarizes concepts outlined in the National Institutes of Health (NIH) consensus statement.1
Compromised bone strength leads to an increased risk of fracture.
Bone strength depends on bone quality and bone density.
Bone quality is affected by the bone architecture and turnover, and the accumulation of bone damage (e.g. micro-fractures) and mineralization.
Bone density is expressed as grams of mineral per area (aBMD) or volume (vBMD)
Though not mentioned in the NIH statement, the quantity as well as the quality of the bone matrix (including type 1 collagen and other proteins) also affects bone quality.
Reference:
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:
NIH Consensus Development Panel. JAMA 2001; 285 (6):

9. Lifetime Changes in Bone Mass
BMD
Gain
Consolidation
Loss
Men
Women
Cancer Treatments
Cancer
Age

10. Interpretation of a DEXA Scan
T score
Z score

11. Diagnosis of Osteoporosis
The WHO and the International Osteoporosis Foundation have developed the following guidelines for women, for assessments with DEXA scanning.
This scale is based on a mean value based on a young female BMD. As a person’s BMD level decreases past this mean value, so their risk of developing osteopenia and/or osteoporosis (and suffering a fracture) increases.
A 1.0 SD (standard deviation) decrease from the mean BMD equals a T-score of -1. A 2.5 SD decrease equals a T-score of -2.5.
Reference:
1. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet Jun 1;359(9321):
Adapted from Kanis, JA. Lancet 2002; 359(9321):

12. BMD and Fracture Risk in the Normal Population
Average
35 years
16X 8X 4X 2X 1X
+1.0
-1.0
-2.0
-3.0
-4.0
T score

13. 80% of Fractures Occur in Patients Who Have Normal or Osteopenic BMD50 45 40 35 30 25 20 15 10 5
Fracture rate per 1,000 person-years
>1.0
1.0 to 0.5
0.5 to 0.0
0.0 to –0.5
–0.5 to –1.0
–1.0 to –1.5
–1.5 to –2.0
–2.0 to –2.5
–2.5 to –3.0
–3.0 to –3.5
< –3.5
450
400
350
300
250
200
150
100 50
Number of women with fractures
Fracture rate
No. of women with fractures
BMD distribution
Fracture rate increases ~2-fold in osteopenic women
Majority of fractures occur in osteopenic women (T-score –1.0 to –2.5)
BMD, bone mineral density. Reprinted from Siris ES, et al. Arch Intern Med. 2004;164(10): 13 13 13

14. Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:3555-61
Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations 40 80
120
160
200
Bioavailable E2, pmol/l
Premenopausal
women
Postmenopausal
Normal
men
Androgen
Deprivation
Therapy
Aromatase
Inhibitor
Therapy
Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:

15. Low Oestrogen Levels Increase Relative Fracture Risk
Women ≥ 65 years with undetectable estrogen levels (< 5 pg/mL) have a 2.5-fold increased risk for subsequent hip or vertebral fracturesa
1.00
Spine fracture
Hip fracture
0.75
0.5
0.5
Relative risk
0.50
0.3
0.3
0.25
0.00
< 5
5 - 6
7 - 9
≥ 10
Endogenous serum estradiol level, pg/mL
a. Compared with women with detectable estrogen levels.
Adapted from Cummings SR, et al. N Engl J Med. 1998;339(11):

16. Normal and Cancer Treatment Related Bone Loss Rates10
Naturally occurring
bone loss
CTIBL
7.7 8
7.0
Bone loss at I year 6 4
2.6
2.0 2
1.0
0.5
Normal
men1
Postmenopausal
Women >551
Menopausal
Women
<551
AI therapy in
postmenopausal women2
AI therapy
plus GnRH agonist in
premenopausal
women3
Premature
menopause
secondary to chemotherapy4
Kanis JA. Osteoporosis.1997:22-55.
Eastell R et al. J Bone Mineral Res
Gnant M. San Antonio Breast Cancer Symposium, 2002.
Shapiro CL et al. J Clin Oncol. 2001;19:

17. Breast Cancer and Bone Health
Normal Bone Health
Impact of Cancer Therapies on Bone Health
Therapeutic Strategies
Management Guidelines

18. Fracture Episode Rates Throughout the ATAC Study4
End of
Treatment
Anastrozole (A) Tamoxifen (T)
146 v 143
fractures 3
Annual fracture episode rates
(%) 2
375 v 234
fractures 1
RR=1.55
P <0.0001
RR=1.03
P =0.79
Key point: The increase in fracture rates appears to only be associated with the active treatment period and does not continue after treatment completion.
Q: Why is the carryover effect not seen with bones ?
Q: Were any of these patients receiving bisphosphonates or other relevant medications ? Q: How do these fracture rates compare with an age-matched population ? Q: Wouldn’t you expect the tamoxifen patients to begin to do worse with respect to fractures as they come off treatment and the protective effect of tamoxifen is lost ? 1 2 3 4 5 6 7 8 9
Time since randomization (years)
At risk: A T
2984
2976
2859
2824
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
1713
1645
702
659
Forbes et al Lancet Oncology 2008 18

19. Fracture Rates in Adjuvant Trials of Aromatase Inhibitors
Tamoxifen /
Placebo
% Increase
Reference
ATAC
(Anastrozole)
340 (11%)
237 (7.7%)
43%
Howell et al Lancet 2005
BIG 1-98
(Letrozole)
211 (8.6%)
141 (5.8%)
50%
Coates et al JCO 2007
IES
(Exemestane)
162 (7.0%)
115 (4.9%)
41%
Coombes et al Lancet 2007
ABCSG (Anastrozole)
34 (2.0%)
16 (1.0%)
113%
Jakesz et al Lancet 2005
MA17
137 (5.3%)
119 (4.6%)
15%
Perez et al
JCO 2006

20. ATAC -Percentage Change in BMD Over Time
Anastrozole (n=81)
Tamoxifen (n=86)
Lumbar spine
Total hip
Estimated % change (mean and 95% CI) 4 4 2 2 -2 -2 -4 -4 -6 -6 -8 -8
-10
-10
Baseline 1 2 5
Baseline 1 2 5
Time (years)
Time (years)
Significantly more BMD loss on anastrozole than tamoxifen
p< for both lumbar spine and total hip BMD primary analysis
No patient with normal baseline BMD developed osteoporosis
Eastell et al J Clin Oncol 26:1051, 2008.

21. Breast Cancer and Bone Health
Normal Bone Health
Impact of Cancer Therapies on Bone Health
Therapeutic Strategies
Management Guidelines

22. Overall Structure of BisphosphonatesPO H 3 2 R
Chain 2 R
Chain 1
Osteoclast C PO H 3 2

23. Z-FAST / ZO-FAST / E-ZO-FAST: Trial design
Key endpoints:
Primary: Bone mineral density (BMD) at 12 mo
Secondary : Fracture, disease recurrence, disease free-survival, bone markers
2,193 patients
Breast cancer
Stage I to IIIa
Postmenopausal or amenorrheic due to cancer treatment
ER+ and/or PgR+
T-score ≥ –2 SD R
Letrozole +
zoledronic acid 4 mg every 6 months
redundant
Letrozole
Delayed zoledronic acid
If 1 of the following occurs:
BMD T-score < –2 SD
Clinical fracture
Asymptomatic fracture at 36 months
Treatment duration 5 years
BMD = Bone mineral density; ER = Oestrogen receptor; PgR = Progesterone receptor; R = Randomisation; SD = Standard deviation. 23 23

24. Z-FAST: Immediate Zoledronic Acid Increases BMD in Lumbar Spine and Hip
Upfront ZOL (4 mg/6 months)
Delayed ZOL (4 mg/6 months)
(N = 602) 4%
P < .0001*
P < .0001*
P < .0001*
P < .0001*
P < .0001*
P < .0001* 3% 2%
Δ 4,4% 1%
Δ 5.9%
Δ 6.7%
Δ 3.3%
Δ 4.7%
Δ 5.2%
Mean (SEM) % change BMD 0%
–1%
–2%
Results from the Z-FAST study show that after 12, 24, and 36 months of therapy, upfront zoledronic acid (4 mg every 6 months) treatment increases bone mineral density (BMD) from baseline at the lumbar spine and total hip
In contrast, the delayed group experienced declines in BMD from baseline at 12 and 24 months at both lumbar spine and total hip
Patients receiving upfront zoledronic acid (4 mg/ 6 months) continued to gain BMD over 2 years of treatment
The overall difference between the upfront and delayed groups was increasing over 24 and 36 months of therapy
–3%
–4%
Month 12†
Month 24†
Month 36‡
Month 12†
Month 24†
Month 36‡
Lumbar spine
Total hip
SEM = Standard error of the mean; BMD = Bone mineral density; ZOL = Zoledronic acid. *P values correspond to intergroup comparisons. †Intragroup comparisons from baseline to month 12 or 24 for all treatment groups were significant (P < for all).
Adapted from Brufsky A, et al. Presented at: 29th SABCS 2006, Abstract #5060. ‡Brufsky A, et al. Presented at: 30th SABCS 2007, Abstract #27. 24 24

25. ARIBON Study Design - Monthly Oral Ibandronate
Lester et al. Clin Cancer Res, in press, 2008

26. ARIBON Study Results - Monthly Oral Ibandronate 150mg
SPINE
HIP
Lester et al. Clin Cancer Res, in press 2008

27. ABCSG-12 - Bone Protection Study with Zoledronic Acid
Premenopausal women with early breast cancer
No chemotherapy
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d
+ Zoledronic Acid 4mg q6m
Surgery
(+RT)
Goserelin
3.6mg q28d
Randomize
1 : 1 : 1: 1
Anastrozole 1 mg/d
Anastrozole 1 mg/d
+ Zoledronic Acid 4mg q6m
Gnant MF, et al. J Clin Oncol. 2007;25: 8

28. ABCSG XII: 6 Monthly Zoledronic Acid Reduces Bone Loss
Ana + ZA: p<0.0001
END OF TREATMENT
Tam + ZA: p=0.049
Tamoxifen alone: p<0.0001
Anastrozole alone: p<0.0001
In the ABCSG-12 trial, premenopausal patients receiving endocrine therapy alone (either tamoxifen + goserelin or anastrozole + goserelin) had 17.3% and 11.6% reductions in bone mineral density (BMD) from baseline, respectively, at 36 months
In contrast, patients who received zoledronic acid (4 mg every 6 months) had BMD measurements that remained stable over 36 months
ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12.
Gnant MF, et al. Lancet Oncology 2008

29. Zoledronic Acid Preserves BMD During 3 Years of Adjuvant Therapy
Goserelin/Anastrozole
Goserelin/Anastrozole + ZOL 20 40 60 80
100 6 12 36
Time, mo
Patients, % 20 40 60 80
100 6 12 36
Time, mo
Patients, %
Osteoporosis
Osteopenia
Normal
BMD = Bone mineral density; ZOL = Zoledronic acid.
Adapted from Gnant MF, et al. J Clin Oncol. 2007;25(7):

30. First DFS Events (ITT Population)
No ZOL vs ZOL
First event per patient, n
H.R. 0.65; p=.017
(n = 904)
(n = 899)
DFS = Disease-free survival; ITT = Intent-to-treat; ZOL = Zoledronic acid.
Gnant M, et al. NEJM 2009

31. Denosumab For Treatment of Bone Loss on Aromatase Inhibitors
RANKL stimulates osteoclasts and bone resorption
Denosumab
Novel fully human monoclonal antibody to RANKL
RANKL
RANK
Cancer Cells in Bone
Direct effects on tumor?
Cytokines and Growth Factors (IL-6, IL-8, IL-1b, PGE-2, TNF-a, CSF-1, PTHrP)
Growth Factors (TGF-b, IGFs, FGFs, PDGFs, BMPs)
Osteoclast
RANKL
RANKL
AI, aromatase inhibitor; BMP, bone morphogeneic protein; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; CSF, colony stimulating factor; PDGF, platelet derived growth factor; PGE, prostaglandin E; PTHrP, parathyroid hormone release hormone; RANKL, receptor activator of NF-κB ligand; TGF tissue growth factor; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.
Bone Resorption
Osteoblast Lineage
Bone

32. Denosumab: Effect on Lumbar Spine Bone Mineral Density
BMD, bone mineral density;
Ellis G, et al. J Clin Oncol 2008

33. Breast Cancer and Bone Health
Normal Bone Health
Impact of Cancer Therapies on Bone Health
Therapeutic Strategies
Management Guidelines

34. ASCO Guidelines on Bone Health
ASCO Guidelines Hillner, B. E. et al. J Clin Oncol; 21:

35. Reid et al. Cancer Treatment Reviews 2008.
UK Management for Bone Loss in Breast Cancer - NOS/NCRI Post-menopausal women >age 45
Baseline DEXA scan and risk assessment if for AI therapy
Risk adapted strategy
Lifestyle advice and adequate calcium and vitamin D
1 g calcium and 800iu vitamin D
Reassure if T score > -1 and no risk factors
No monitoring required
Monitor BMD of osteopaenic patients every 2 years
Baseline T score <-1
Intervention with bisphosphonates
> age 75 and > 1 risk factor for osteoporotic fracture
T score < -2 either at baseline or on follow-up
T score < -1 at baseline and annual bone loss >4%
Reid et al. Cancer Treatment Reviews 2008.

36. UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer
POST-MENOPAUSAL WOMEN
Reid et al. Cancer Treatment Reviews 2008

37. Reid et al. Cancer Treatment Reviews 2008
UK Management for Bone Loss in Breast Cancer - NOS/NCRI Premature menopause at age <45
Baseline DEXA scan and risk assessment
Lifestyle advice and adequate calcium and vitamin D
1g calcium and 800iu vitamin D
Risk adapted strategy
Reassure if T score > -1 and not on concomitant AI
No monitoring required
Monitoring of BMD
Perform every 2 years if:
T score < -1 without an AI
All patients if concomitant AI
Intervention with bisphosphonates
Concomitant AI and T score < -1
T score < -2 either at baseline or on follow-up
Annual bone loss >4% on serial BMD monitoring
Reid et al. Cancer Treatment Reviews 2008

38. UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer
PREMATURE MENOPAUSE BEFORE AGE 45
Reid et al. Cancer Treatment Reviews 2008

39. European Recommendations for Women Initiating Aromatase Inhibitor Therapy
Any 2 of the following risk factors:
T-score < –1.5
Age > 65 years
Low BMI (< 20 kg/m2)
Family history of hip fracture
Personal history of fragility fracture after age 50
Oral corticosteroid use of > 6 months
Smoking (current or history of)
T-score ≥ –2.0, no risk factors
T-score < –2.0
Calcium and vitamin D supplements
Zoledronic acid (4 mg / 6 months) calcium and vitamin D supplements
Monitor risk status and BMD every 1 to 2 yearsa
Monitor BMD every 2 years
Data for oral bisphosphonates are emerging
Evidence from 4 clinical trials indicates that zoledronic acid prevents AI-associated bone loss
a. ≥ 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 mo). Use lowest T-score from 3 sites. BMI = Body mass index; BMD = Bone mineral density; AI = Aromatase inhibitor. Adapted from Hadji P, et al. Ann Oncol. 2008;19(8):

40. WHO FRAX Index (www.shef.ac.uk/FRAX)
SPEAKER’S NOTES:
This slide summarizes the musculoskeletal and other adverse events for patients on the IES at 55.7 months follow-up.
Incidence rates per 1000 women years (99% CI) for fractures (allowing more than one fracture event per patient) are E=19.2 (15.9, 23.1) and T=15.1 (12.2, 18.7).
Fracture rates, osteoporosis, and musculoskeletal adverse events all differ between treatment arms, with the majority in favor of tamoxifen.
Muscle cramps significantly favors exemestane (P≤0.001).
Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision.
Reference
1. Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007;369: .

41. Bone Metastases in Cancer
BM are frequent in metastatic cancers; there are various types (lytic, blastic).

42. Consequences of Bone Metastases
Poor functional
capacity
Economic Burden
Impaired
mobility
Severe
bone pain
Metastatic
Bone Disease
Long and painful
recovery from
fractures
Hypercalcaemia
Inconvenient
hospital/clinic
visits
Pain and paralysis
from spinal cord
compression

43. Bone Metastases Can Lead to SREs
Patients who will likely develop an SRE without treatment
% of patients
Left untreated, patients with bone metastases are at high risk of experiencing an SRE, such as pathologic fracture or spinal cord compression. This chart shows the incidence of SREs in patients with bone metastases from various tumor types without treatment. A majority of untreated patients with renal cell carcinoma1 or multiple myeloma2 experienced an SRE, as did half of patients with breast cancer3 and nearly half of patients with prostate cancer4 or non-small cell lung cancer (NSCLC).5
References: 1. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98: Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol. 1998;16: Kohno N, Aogi K, Minami H, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2005;23: Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96: Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:
Renal cell
carcinoma
(n=74)
Multiple
myeloma
(n=179)
Breast
(n=114)
Prostate
(n=208)
NSCLC
(n=250)
Data are from placebo-controlled arms of bisphosphonate trials.
Lipton A et al. Cancer. 2003;98: Berenson JR et al. J Clin Oncol. 1998;16: Kohno N et al. J Clin Oncol. 2005;23: Saad F et al. J Natl Cancer Inst. 2004;96: Rosen LS et al. Cancer. 2004;100:

44. The Vicious Cycle of Bone Destruction
Growth factors and cytokines released by tumor cells
Tumor Cells
Osteoclastic resorption stimulated
PTHrP
IL-6
IL-8, PGE2 TNF- CSF-1
BMP
PDGF
FGFs
IGFs
TGF-β
Peptides (eg, TGF-β) released by bone resorption
Tumor cell production of factors increased
More bone resorption
Tumor cell proliferation
Osteoclast
Bone
Adapted from Mundy GR, Yoneda T.
N Engl J Med. 1998;339:
Courtesy John Mackey 44

45. Effect of Bisphosphonates on Vicious Cycle of Bone Destruction
Decrease activity of osteoclasts
Tumor Cells
PTHrP
IL-6
IL-8, PGE2 TNF- CSF-1
Reduction in release of peptides
BMP
PDGF
FGFs
IGFs
TGF-β
BMP
PDGF
FGFs
IGFs
TGF-β
Slowed tumor-cell growth
Reduced production of PTHrP and other factors
Osteoclast
Decrease in bone resorption
Bone
Adapted from Mundy GR, Yoneda T.
N Engl J Med. 1998;339:
Courtesy John Mackey 45

46. Added Benefit of Zoledronic Acid Over Pamidronate in Breast Cancer
64% risk of skeletal complication with no bisphosphonate at 2 years
Approx 33% risk reduction with pamidronate
Further 20% risk reduction with zoledronic acid
64%
43%
34%
Lipton A, et al Cancer 2000; 88: ; Rosen LS, et al Cancer 2003;100:36-43.

47. Conclusions Important effects of cancer treatments on bone health
Ovarian suppression
Aromatase inhibitors
Effective management and treatment strategies emerging
DEXA baseline assessment required
Risk adapted monitoring and intervention
Bisphosphonates effective in preventing bone loss
Bone metastases cause considerable morbidity
Bisphosphonates markedly reduce number and severity of skeletal complications